AR is a ligand-activated steroid hormone receptor which functions as a transcription factor in prostate cells to regulate myriad genes involved in cell division, apoptosis and angiogenesis (Compagno et al., PLoS One, 2: e1006). Prostate carcinomas are initially androgen-dependent and, therefore, responsive to therapies that reduce or eliminate AR activation. Specifically, a variety of approaches aimed at manipulating the effects of androgen have been shown unequivocally to be efficacious in the treatment of prostatic carcinoma. Historically, orchiectomy and the administration of estrogen were first demonstrated to have beneficial effects. However, prostate cancers often escape from such treatments and recur (Heinlein and Chang, Endocr Rev 25: 276-308).
Gonadotropin-releasing hormone agonists (GnRH agonists) and antiandrogens have been shown to be safe and effective in multiple settings and have become the standards of care for patients at high risk of recurrence after initial surgery or radiotherapy or who recur after these procedures (Scher and Sawyers. Journal of Clinical Oncology, 23: 8253-8261; Baltogiannis et al. Experimental Oncology, 26: 185-191; National Comprehensive Cancer Network (2008). Practice guidelines in oncology, 1.2008, 1-44; Bhandari et al. Journal of Clinical Oncology, 23: 8212-8218; Clinical Care Options & Postgraduate Institute for Medicine (2006). Recent and Future Directions of Hormonal Therapy in Prostate Cancer. 1-22; Evans et al. BJU International, 95: 743-479; Use of 5-alpha-reductase inhibitors for prostate cancer chemoprevention: American society of clinical oncology/American urological association 2008 clinical practice guideline summary, (2009, May) Journal of Oncology Practice, 5: 127-129; O'Connor and Fitzpatrick. BJU International, 95: 22-28; Koltz and Schellhammer Combined androgen blockade: worth a second look. 1-17). Many studies have evaluated the development of resistance in patients receiving endocrine manipulations, and it is clear that potential reasons for the resistance seen with endocrine manipulation therapies include: increased expression of the androgen receptor, increased sensitivity of the androgen receptor, and increased local production of androgens by cells not sensitive to existing inhibitors. Recently, antiandrogens have been shown to have activity in patients with resistance to standard methods of treating prostatic cancer, further validating the role of this receptor even in patients who appear to have “castration-resistant” prostatic cancer. It appears clear that even in patients whose tumors fail to respond to standard therapies, inhibition of the androgen receptor directly by dsRNA agents directed to this target should be active and, because of the increased androgen receptor expression that characterizes prostate cancers resistant to traditional therapies, may be more active in subjects harboring resistant cancers than earlier stages of disease.
Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35 nucleotides have been described as effective inhibitors of target gene expression in mammalian cells (Rossi et al., U.S. Patent Application Nos. 2005/0244858 and US 2005/0277610). dsRNA agents of such length are believed to be processed by the Dicer enzyme of the RNA interference (RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA” (“DsiRNA”) agents. Additional modified structures of DsiRNA agents were previously described (Rossi et al., U.S. Patent Application No. 2007/0265220).